Vascular contributions to dementia and AD are increasingly recognized. Thus, the focus of this entire program and Project 1 is on the ?neurovascular hypothesis?, which holds that dysfunction in the cerebral vascular system contributes to cognitive decline, dementia and AD. Major genetic risk factors for late-onset AD, i.e., apolipoprotein E-?4 (APOE4) gene, and early-onset autosomal dominant AD, i.e., presenilin 1 (PSEN1) mutations, exert direct toxic effects on the cerebrovascular system and neurons, and influence amyloid-? (A?) metabolism and clearance, and tau pathology. However, the role of cerebrovascular changes in disease pathogenesis, and in predicting neuronal injury, neurodegeneration and cognitive decline in individuals with genetic risk for AD remains elusive. Based on published data and our preliminary findings, we hypothesize that neurovascular dysfunction and breakdown in the blood-brain barrier (BBB) are detectable by molecular and imaging biomarkers early in the disease process in APOE4 and PSEN1 mutation carriers relative to non-carriers, and predict neuronal injury, disrupted brain connectivity and cognitive decline. To test our hypothesis we will evaluate 294 APOE4 carriers and 340 non-carriers ages 45-90, and 44 PSEN1 mutation carriers and 44 non-carriers ages 18 and older, at early stages with no or mild cognitive impairment that will be followed longitudinally over 4-5 years. We will use: 1) a novel molecular biomarker assessment of the neurovascular unit (NVU) in biofluids (CSF and plasma) to determine how vascular/BBB injury relates to neuronal injury and responses of non-neuronal neighboring cells (e.g., astrocytes, microglia, inflammatory response), A? and tau biomarkers; 2) advanced neuroimaging assessment of neurovascular function using a novel dynamic contrast enhanced magnetic resonance imaging protocol (DCE-MRI) to examine regional BBB permeability in relation to cerebral blood flow (CBF; arterial spin labeling, ASL-MRI), white matter lesion (WML) pathology, and structural/functional connectivity (Project 2 collaboration); 3) cognitive assessment by Uniform Data Set and other neuropsychological measures of memory. Four aims will test our hypothesis in APOE4 and PSEN1 mutation carriers and non-carriers to 1) Evaluate NVU molecular biomarkers in biofluids in relation to cognitive function (AIM 1); 2) Determine regional BBB permeability (DCE-MRI) in relation to NVU molecular biomarkers and cognitive decline (AIM 2); 3) Examine the temporal relationship between BBB permeability (DCE-MRI), CBF (ASL-MRI) and WML (AIM 3); and 4) Evaluate NVU molecular biomarkers in biofluids in relation to structural/functional connectivity (AIM 4; Project 2 collaboration). The relationship between neurovascular integrity, brain connectivity and cognitive function has not been explored. This project will apply a hypothesis-driven approach to understand how neurovascular integrity changes in individuals with genetic risk for AD, and whether it can predict cognitive decline, thus allowing the discovery of new diagnostic tools and potential new therapeutic targets and treatment opportunities within the vascular system to prevent dementia and AD.